Pancreas

Anatomy

the pancreas lies in the epigastrium and left

hypochondrium areas of the abdomen

The head lies within the concavity

of the duodenum
 Physiologic Anatomy of the Pancreas
The pancreas is a dual-function gland,
having features of both endocrine and
.exocrine glands

The pancreas is composed of two

major types of Tissues:

(1) the acini, which secrete digestive

juices into the duodenum

(2) the islets of Langerhans, which

secrete insulin and glucagon directly into
the blood.

There are about one million islets distributed throughout the pancreas of a healthy
adult human.
The islets of Langerhans constitute approximately 1 to 2% of the mass of the
pancreas. The combined mass of the islets is 1 to 1.5 grams.
Cell types
Hormones produced in the islets of Langerhans are secreted directly into the
blood flow by (at least) five different types of cells.
• Alpha cells producing glucagon (15–20% of total islet cells)
• Beta cells producing insulin and amylin (65–80%)
• Delta cells producing somatostatin (3–10%)
• PP cells (gamma cells) producing pancreatic polypeptide (3–5%)
• Epsilon cells producing ghrelin (<1%)
Insulin Chemistry and Synthesis
It is composed of two amino acid
chains, connected to each other by disulfide
linkages.

Insulin is synthesized in the beta cells

to form an insulin preprohormone.

Then cleaved in the endoplasmic

reticulum to form a proinsulin

most of this is further cleaved in the

Golgi apparatus to form insulin and peptide
fragments before being packaged in the
secretory granules.
 Insulin receptors
• Insulin binds to the α-subunit of its receptor, which causes
autophosphorylation of the ᵦ- subunit receptor. which in turn induces
tyrosine kinase activity.

• The receptor tyrosine kinase activity begins a cascade of cell

phosphorylation that increases or decreases the activity of
enzymes, including insulin receptor substrates, that mediate the
effects on glucose, fat, and protein metabolism.

• For example, glucose transporters are moved to the cell

membrane to facilitate glucose entry into the cell.
Effect of Insulin on Carbohydrate Metabolism
• Insulin Promotes Muscle Glucose Uptake and Metabolism
• Storage of Glycogen in Muscle
• Insulin Promotes Liver Uptake, Storage, and Use of Glucose
The mechanism by which insulin causes glucose uptake and storage in the liver
includes several almost simultaneous steps:
1. Insulin inactivates liver phosphorylase, the principal enzyme that causes liver
glycogen to split into glucose. This prevents breakdown of the glycogen that has
been stored in the liver cells.
2. Insulin causes enhanced uptake of glucose from the blood by the liver cells. It
does this by increasing the activity of the enzyme glucokinase, which is one of the
enzymes that causes the initial phosphorylation of glucose after it diffuses into the
liver cells. Once phosphorylated, the glucose is temporarily trapped inside the liver
cells because phosphorylated glucose cannot diffuse back through the cell
membrane.
3. Insulin also increases the activities of the enzymes that promote glycogen
synthesis, including especially glycogen synthase, which is responsible for
polymerization of the monosaccharide units to form the glycogen molecules. The net
effect of all these actions is to increase the amount of glycogen in the liver.
• Glucose Is Released from the Liver Between Meals
When the blood glucose level begins to fall to a low level between meals, several
events transpire that cause the liver to release glucose back into the circulating
blood:
1. The decreasing blood glucose causes the pancreas to decrease its insulin
secretion.
2. The lack of insulin then reverses all the effects listed earlier for glycogen
storage, essentially stopping further synthesis of glycogen in the liver and
preventing further uptake of glucose by the liver from the blood.
3. The lack of activates the enzyme phosphorylase, which causes the splitting of
glycogen into glucose phosphate.
4. The enzyme glucose phosphatase, which had been inhibited by insulin, now
becomes activated by the insulin lack and causes the phosphate radical to split
away from the glucose; this allows the free glucose to diffuse back into the blood.
Thus, the liver removes glucose from the blood when it is present in excess after a
meal and returns it to the blood when the blood glucose concentration falls
between meals

• Insulin Promotes Conversion of Excess Glucose into Fatty Acids

and Inhibits Gluconeogenesis in the Liver
Effect of Insulin on Fat Metabolism
• Insulin Promotes Fat Synthesis and Storage
The different factors that lead to increased fatty acid synthesis in the liver include
the following:
1. Insulin increases the transport of glucose into the liver cells. The glucose is first
split to pyruvate in the glycolytic pathway, and the pyruvate subsequently is
converted to acetyl coenzyme A (acetyl-CoA), the substrate from which fatty acids
are synthesized.
2. An excess of citrate and isocitrate ions is formed by the citric acid cycle when
excess amounts of glucose are being used for energy. These ions then have a direct
effect in activating acetyl-CoA carboxylase, the enzyme required to carboxylate
acetyl-CoA to form malonyl-CoA, the first stag of fatty acid synthesis.
3. Most of the fatty acids are then synthesized within the liver itself and used to
form triglycerides, the usual form of storage fat. They are released from the liver
cells to the blood in the lipoproteins. Insulin activates lipoprotein lipase in the
capillary walls of the adipose tissue, which splits the triglycerides again into fatty
acids, a requirement for them to be absorbed into the adipose cells, where they are
again converted to triglycerides and stored.
• Insulin Deficiency Increases Use of Fat for Energy
1. Insulin Deficiency Causes Lipolysis of Storage Fat and Release of Free Fatty
Acids. The most important effect is that the enzyme hormone-sensitive lipase
in the fat cells becomes strongly activated. This causes hydrolysis of the stored
triglycerides, releasing large quantities of fatty acids and glycerol into the
circulating blood. Consequently, the plasma concentration of free fatty acids
begins to rise within minutes. This free fatty acid then becomes the main
energy substrate used by essentially all tissues of the body besides the brain.
2. Insulin Deficiency Increases Plasma Cholesterol and Phospholipid
Concentrations.
3. Excess Usage of Fats During Insulin Lack Causes Ketosis and Acidosis
In the absence of insulin but in the presence of excess fatty acids in the liver cells In
the mitochondria, beta oxidation of the fatty acids then proceeds very rapidly,
releasing extreme amounts of acetyl-CoA. A large part of this excess acetyl-CoA is
then condensed to form acetoacetic acid, which in turn is released into the
circulating blood.in severe diabetes the acetoacetic acid and the b-hydroxybutyric
acid can cause severe acidosis and coma, which often leads to death.
Effect of Insulin on Protein Metabolism and on Growth
• Insulin Promotes Protein Synthesis and Storage
The mechanisms in which insulin causes protein storage are:
1. Insulin stimulates transport of many of the amino acids into the cells.
2. Insulin increases the translation of messenger RNA, thus forming new proteins.
3. Over a longer period of time, insulin also increases the rate of transcription of
selected DNA genetic sequences in the cell nuclei, thus forming increased
quantities of RNA and still more protein synthesis.
4. Insulin inhibits the catabolism of proteins.
5. In the liver, insulin depresses the rate of gluconeogenesis. Because the substrates
most used for synthesis of glucose by gluconeogenesis are the plasma amino acids,
this suppression of gluconeogenesis conserves the amino acids in the protein
stores of the body.
• Insulin Lack Causes Protein Depletion and Increased Plasma Amino
Acids. The plasma amino acid concentration rises considerably, and most of the
excess amino acids are used either directly for energy or as substrates for
gluconeogenesis
• Insulin and Growth Hormone Interact Synergistically to Promote
Growth
Mechanisms of Insulin Secretion
 Control of Insulin Secretion
Table : Summarizes some of the factors that can increase or decrease insulin secretion.
Glucagon and Its Functions
• Glucagon, a polypeptide hormone secreted by the alpha cells of
the islets of Langerhans when the blood glucose concentration
falls, has several functions that are diametrically opposed to those
of insulin.
• Most important of these functions is to increase the blood glucose
concentration, an effect that is exactly the opposite that of insulin.
For this reason, glucagon is also called the hyperglycemic hormone.
Effects on Glucose Metabolism
• Glucagon Causes Glycogenolysis and Increased Blood Glucose
Concentration
The most dramatic effect of glucagon is its ability to cause
glycogenolysis in the liver, which in turn increases the blood glucose
concentration within minutes.
It does this by the following complex cascade of events:
1. Glucagon activates adenylyl cyclase in the hepatic cell membrane
2. Which causes the formation of cyclic adenosine Monophosphate
3. Which activates protein kinase regulator protein,
4. Which activates protein kinase,
5. Which activates phosphorylase b kinase,
6. Which converts phosphorylase b into phosphorylase a
7. Which promotes the degradation of glycogen into glucose-1-
phosphate,
8. Which then is dephosphorylated; and the glucose is released
from the liver cells.
• Glucagon Increases Gluconeogenesis
Glucagon increases the rate of amino acid uptake by the liver cells
and then the conversion of many of the amino acids to glucose by
gluconeogenesis. This is achieved by activating multiple enzymes that
are required for amino acid transport and gluconeogenesis
Other Effects of Glucagon
the most important effect is that glucagon activates adipose cell
lipase, making increased quantities of fatty acids available to the
energy systems of the body. Glucagon also inhibits the storage of
triglycerides in the liver, which prevents the liver from removing fatty
acids from the blood; this also helps make additional amounts of fatty
acids available for the other tissues of the body.
Glucagon in very high concentrations also (1) enhances the strength of
the heart; (2) increases blood flow in some tissues, especially the
kidneys; (3) enhances bile secretion; and (4) inhibits gastric acid
secretion. All these effects are probably of minimal importance in the
normal function of the body.
Regulation of Glucagon Secretion
• Increased Blood Glucose Inhibits Glucagon Secretion the effect of
blood glucose concentration on glucagon secretion is in exactly the
opposite direction from the effect of glucose on insulin secretion.
• Increased Blood Amino Acids Stimulate Glucagon Secretion.
High concentrations of amino acids stimulate the secretion of
glucagon. This is the same effect that amino acids haven in stimulating
insulin secretion. Thus, in this instance, the glucagon and insulin
responses are not opposites.
The importance of amino acid stimulation of glucagon secretion is
that the glucagon then promotes rapid conversion of the amino acids
to glucose, thus making even more glucose available to the tissues.
Exercise Stimulates Glucagon Secretion
One of the factors that might increase glucagon secretion in exercise
is increased circulating amino acids. Other factors, such as b-
adrenergic stimulation of the islets of Langerhans, may also play a
role.
Somatostatin
The delta cells of the islets of Langerhans secrete the hormone somatostatin, a
polypeptide containing only 14 amino acids that has an extremely short half-life
of only 3 minutes in the circulating blood. Almost all factors related to the
ingestion of food stimulate somatostatin secretion. They include (1) increased
blood glucose, (2) increased amino acids, (3) increased fatty acids, and (4)
increased concentrations of several of the gastrointestinal hormones released
from the upper gastrointestinal tract in response to food intake.
In turn, somatostatin has multiple inhibitory effects as follows:
1. Somatostatin acts locally within the islets of Langerhans themselves to
depress the secretion of both insulin and glucagon.
2. Somatostatin decreases the motility of the stomach, duodenum, and
gallbladder.
3. Somatostatin decreases both secretion and absorption in the gastrointestinal
tract.

It should also be recalled that somatostatin is the same chemical substance as

growth hormone inhibitory hormone, which is secreted in the hypothalamus and
suppresses anterior pituitary gland growth hormone secretion.
Diabetes Mellitus
Diabetes mellitus is a syndrome of impaired carbohydrate, fat, and protein
metabolism caused by either lack of insulin secretion or decreased sensitivity of
the tissues to insulin. There are two general types of diabetes mellitus:
1. Type I diabetes, also called insulin-dependent diabetes mellitus (IDDM), is
caused by lack of insulin secretion.
2. Type II diabetes, also called non–insulin-dependent diabetes mellitus
(NIDDM), is caused by decreased sensitivity of target tissues to the
metabolic effect of insulin. This reduced sensitivity to insulin is often called
insulin resistance.
• Type I Diabetes—Lack of Insulin Production by Beta Cells of the Pancreas
Injury to the beta cells of the pancreas or diseases that impair insulin
production can lead to type I diabetes. Viral infections or autoimmune
disorders may be involved in the destruction of beta cells in many patients with
type I diabetes, although heredity also plays a major role in determining the
susceptibility of the beta cells to destruction by these insults.
• Blood Glucose Concentration Rises to Very High Levels in Diabetes
Mellitus
• Increased Blood Glucose Causes Loss of Glucose in the Urine
• Increased Blood Glucose Causes Dehydration
• Diabetes Mellitus Causes Increased Utilization of Fats and
Metabolic Acidosis.
The shift from carbohydrate to fat metabolism in diabetes increases
the release of keto acids, such as acetoacetic acid and b-
hydroxybutyric acid, into the plasma more rapidly than they can be
taken up and oxidized by the tissue cells. As a result, the patient
develops severe metabolic acidosis from the excess keto acids, which,
in association with dehydration due to the excessive urine formation,
can cause severe acidosis. This leads rapidly to diabetic coma.

• Diabetes Causes Depletion of the Body’s Proteins

• Type II Diabetes—Resistance to the Metabolic Effects of Insulin
Type II diabetes is far more common than type I, accounting for about 90 per cent
of all cases of diabetes mellitus. In most cases, the onset of type II diabetes
occurs after age 30, often between the ages of 50 and 60 years, and the disease
develops gradually. Therefore, this syndrome is often referred to as adult-onset
diabetes.
Type II diabetes, in contrast to type I, is associated with increased plasma
insulin concentration (hyperinsulinemia).This occurs as a compensatory
response by the pancreatic beta cells for diminished sensitivity of target
tissues to the metabolic effects of insulin, a condition referred to as insulin
resistance. Insulin resistance is part of a cascade of disorders that is often
called the “metabolic syndrome.” Some of the features of the metabolic
syndrome include: (1) obesity, especially accumulation of abdominal fat;
(2) insulin resistance; (3) fasting hyperglycemia; (4) lipid abnormalities
such as increased blood triglycerides and decreased blood high-density
lipoprotein-cholesterol; and (5) hypertension. All of the features of the
metabolic syndrome are closely related to excess weight gain, especially
when it is associated with accumulation of adipose tissue in the
abdominal cavity around the visceral organs.